REVIEWS Coronaviruses — drug discovery and therapeutic options Alimuddin Zumla1*, Jasper F. W. Chan2*, Esam I. Azhar3*, David S. C. Hui4* and Kwok-Yung Yuen2* Abstract | In humans, infections with the human coronavirus (HCoV) strains HCoV‑229E, HCoV‑OC43, HCoV‑NL63 and HCoV‑HKU1 usually result in mild, self‑limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, respectively, have received global attention over the past 12 years owing to their ability to cause community and health‑care‑associated outbreaks of severe infections in human populations. These two viruses pose major challenges to clinical management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiology, virology, clinical features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus‑based and host‑based therapeutic options for CoV infections. Coronaviruses (CoVs; subfamily Coronavirinae, family SARS in Hong Kong and other regions10,11,18–21. The high Coronaviridae, order Nidovirales) are a group of highly infectivity of SARS was highlighted by the super-spread- diverse, enveloped, positive-sense, single-stranded ing event at a major teaching hospital in Hong Kong in RNA viruses that cause respiratory, enteric, hepatic which 138 people, including many previously healthy and neurological diseases of varying severity in a broad health-care workers, were infected within 2 weeks of range of animal species, including humans1–3. CoVs exposure to an index patient who was being managed in are subdivided into four genera: Alphacoronavirus, a general medical ward for community-acquired pneu- Betacoronavirus (βCoV), Gammacoronavirus and monia10,22. Through international air travel, SARS-CoV Deltacoronavirus2–7. Over the past 12 years, two novel was spread to 29 countries and regions with a total of βCoVs, severe acute respiratory syndrome CoV (SARS- 8,098 cases and 774 fatalities (9.6% of cases) by the end CoV) and Middle East respiratory syndrome CoV of the epidemic in July 2003 (REF. 23) (see Supplementary (MERS-CoV), have emerged, and these viruses can information S1 (figure, parts a,b)). cause severe human diseases8,9. The lack of effective drug A retrospective serological survey suggested that treatment and associated high morbidity and mortality cross-species transmission of SARS-CoV or its variants rates of these two CoVs as well as their potential to cause from animal species to humans might have occurred fre- epidemics highlight the need for novel drug discovery quently in the wet market, where high seroprevalence for the treatment of CoV infections. was detected among asymptomatic animal handlers24. A close variant of SARS-CoV was isolated in palm civets Epidemiology of SARS and MERS in Dongmen market, Shenzhen, China, in 2003 (REF. 25). SARS. SARS-CoV emerged first in southern China During the small-scale SARS outbreaks in late 2003 and and rapidly spread around the globe in 2002–2003 early 2004, three of the four patients had direct or indi- (REFS 8,10,11). In November 2002, an unusual epidemic rect contact with palm civets26,27. However, viral genetic of atypical pneumonia with a high rate of nosocomial sequence analysis demonstrated that the SARS-CoV- transmission to health-care workers occurred in Foshan, like virus had not been circulating among masked palm 12,13 *All authors contributed Guangdong, China . In March 2003, a novel CoV civets in markets for a long time, and a serological study equally to this work. was confirmed to be the causative agent for SARS, and was showed that only caged market civets and not wild civets 14–17 28 Correspondence to K.-Y.Y. thus named SARS-CoV . A 64-year-old nephrologist were infected with the SARS-CoV-like virus . CoVs that [email protected] who travelled from southern China to Hong Kong on are highly similar to SARS-CoV have been isolated from doi:10.1038/nrd.2015.37 21 February 2003 became the index case of subsequent Chinese horseshoe bats since 2005 (REFS 29–32). These Published online 12 Feb 2016 large community and health-care-associated outbreaks of SARS-like CoVs from bats share 88–95% sequence NATURE REVIEWS | DRUG DISCOVERY VOLUME 15 | MAY 2016 | 327 ©2016 Mac millan Publishers Li mited. All ri ghts reserved. REVIEWS Zoonotic virus homology with human or civet CoV isolates, which of transmission and other potential sources of MERS- A virus that can transmit suggests that bats were probably the natural reservoir of CoV for optimization of treatment and prevention an infectious disease from a close ancestor of SARS-CoV4,33,34. strategies for MERS56,57. animals (usually vertebrates) to humans. MERS. The isolation of a novel βCoV from a patient Clinical features of SARS and MERS. Patients with SARS in Jeddah, Saudi Arabia, who died of severe pneumonia or MERS present with various clinical features, ranging and multi-organ failure in June 2012, was first reported from asymptomatic or mild respiratory illness to fulmi- in September 2012 (REF. 35). Initially named ‘human nant severe acute respiratory disease with extrapulmo- coronavirus Erasmus Medical Center’, the virus was nary manifestations8,9. Both diseases have predominantly later renamed MERS-CoV by international consensus, respiratory manifestations, but extrapulmonary features and the disease was called Middle East respiratory syn- may occur in severe cases56 (see Supplementary infor- drome (MERS)36. Retrospective analysis of a cluster of mation S2 (table)). Notably, early treatment is especially nosocomial cases in April 2012 in Jordan confirmed that important for patients with severe MERS because this MERS-CoV was also responsible for that outbreak37. disease progresses to respiratory distress, renal failure Over the past 3 years, MERS-CoV has continued to and death much more rapidly than SARS does. The spread within and beyond the Middle East, and there three- to four-fold higher case-fatality rate of MERS rel- are ongoing reports of sporadic cases and community ative to SARS may be related to the higher median age and health-care-associated clusters of infected individu- and prevalence of comorbidities in patients with MERS als in the Middle East, especially in Saudi Arabia and the as well as the different pathogenesis of the two dis- United Arab Emirates9,38. Travel-related cases and clus- eases9,58–61. Comorbidities associated with severe MERS ters have also been increasingly reported on other include obesity, diabetes mellitus, systemic immuno- continents9. As of 9 October 2015, 1,593 laboratory- compromising conditions and chronic cardiac and pul- confirmed cases of MERS, including 568 deaths, have monary diseases9,60,62,63. Although the rate of secondary been reported to the World Health Organization39 (see transmission among household contacts of index MERS Supplementary information S1 (figure, parts c,d)). patients (which is approximately 4%) and the estimated MERS-CoV is considered primarily to be a zoonotic pandemic potential of MERS-CoV are lower than those virus that has the capability of non-sustained person- of SARS-CoV, the rapidly progressive clinical course and to‑person spread9. Serological and virological studies high fatality of MERS continues to pose a major threat to have shown that camels and bats are the most likely at-risk populations64–71 (see Supplementary information animal reservoirs of MERS-CoV9,40–47. Although not all S2 (table)). primary cases of MERS were individuals who had direct contact with camels, such exposure is considered to be Current management strategies for SARS and MERS. an important factor for the spread of MERS-CoV, as Supportive care — including organ support and preven- evidenced by the substantially increased sero­prevalence tion of complications, especially acute respiratory dis- of anti-MERS-CoV antibodies among individuals tress syndrome, organ failure and secondary nosocomial with occupational exposure to camels, such as camel infections — remains the most important management shepherds and slaughterhouse workers, relative to strategy for SARS and MERS, as there is currently no the general population in Saudi Arabia48,49. Person- specific antiviral treatment that has been proven to to‑person transmission of MERS-CoV has occurred be effective in randomized controlled trials8,9,56,72–75. in health-care facilities and family clusters50–53. The Numerous compounds have been found to inhibit the recent, large health-care-associated outbreaks in Jeddah entry and/or replication of SARS-CoV and MERS-CoV and South Korea have been attributed to poor com- in cell culture or in animal models, but activity in vitro pliance with infection control measures54,55. Further and even in animal experiments does not necessarily studies are needed to fully understand the exact mode translate into efficacy in humans8,9. Owing to the high morbidity and mortality rates of SARS and MERS, some of these antiviral drugs and immunomodulators Author addresses have been used empirically or evaluated in uncontrolled 8,10,21,72–90 1Division of Infection and Immunity, University College London, and NIHR Biomedical trials (TABLE 1). Substantial efforts are underway Research Centre, UCL Hospitals NHS Foundation Trust, 307 Euston Road, London to discover new therapeutic agents for CoV infections NW1 3AD, UK. and these investigations are based on our understanding 2State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, of the basic virology of CoVs. Importantly, treatment Research Centre of Infection and Immunology, Department of Microbiology, with these investigational therapies requires appli- University Pathology Building, Queen Mary Hospital, The University of Hong Kong, cation of standard research treatment protocols and 102 Pokfulam Road, Pokfulam, Hong Kong Special Administrative Region of the systematic clinical and virological data collection in People’s Republic of China.